N-lower alkenyl-2,3-dihydro-2-oxo-5-phenyl-1h-1,4-benzodiazepine-1-carboxamides

ABSTRACT

WHEREIN R2, R3, R4, R5, and R6 have the values of above, with an alkenyl, cycloalyl, or haloalkyl isocyanate. The products of formula II are useful as tranquilizers and sedatives.   WHEREIN R1 is alkenyl of three to eight carbon atoms, inclusive, cycloalkyl of three to six carbon atoms, inclusive, and haloalkyl, in which the alkyl group is of two to six carbon atoms, inclusive and the halogen is fluorine, chlorine, bromine, or iodine; wherein R2, R3, R4, and R5 are selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, fluorine, chlorine, bromine, cyano and trifluoromethyl, and wherein R6 is hydrogen or alkyl of one to three carbon atoms, inclusive, and the pharmacologically acceptable acid addition salts thereof, are prepared by reacting a compound of the structure A 2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepin-1-carboxamide of the formula:

United States Patent 1 [111 Mmooo Moffett 1 Feb. 27, I973 N-LOWERALKENYL-2,3-DIHYDRO-2- iL OXO-5-PHENYL-lH-1,4- OBENZODIAZEPINE-l-CARBOXAMIDES I;I- [75] Inventor: Robert B. Moffett,Kalamazoo, F 3

Mich. =7? H [73] Assrgnee: The Upjohn Company, Kalamazoo, Mich. I v 22Filed: Oct. 5, 1970 5 [21] Appl. No.: 78,167 1[ thereof, [52] US. Cl...260/239.3 D, 424/244 wherein R is alkenyl of three to eight carbonatoms, [51] Int. Cl. ..C07d 53/06 inclusive, cycloalkyl of three to sixcarbon atoms, in-

58 Field 0! Search ..260/239.3 o elusive, and haloalkyl, in which thealkyl group is of two to six carbon atoms, inclusive and the halogen isfluorine, chlorine, bromine, or iodine; wherein R R References Clted Rand R are selected from the group consisting of hydrogen, alkyl of oneto three carbon atoms, inclu- UNITED STATES PATENTS sive, fluorine,chlorine, bromine, cyano and 3,236,838 2/1 966 Archer et al. ..260/239.3Irifluoromethyl, and wherein 8 is hydrogen or alkyl 7 c i of one tothree carbon atoms, inclusive, and the phar- OTI-IER PUBLICATIONSmacologically acceptable acid addition salts thereof, ChemicalAbstracts, Vol. 72, Item l328l0k 1970 are pepared by reacting aStructure Abstracting Japanese Patent 70 06,544, Mar. 5, 1970 n ChemicalAbstracts, Vol. 71, Item 39021y (1969) Abstracting South African Patent68 01,890, Nov. 4, T I

Primary Examiner-Henry R. Jiles I Assistant Examiner-R0bert T. BondAttorneyI-Ians L. Berneis and John Kekich TR, 57 ABSTRACT V I wherein RR R and R have the values of t i gg figgafg z fiifigy bmvmdazepm above,with an alkenyl, cycloalyl, or haloalkyl isocyanate. The products offormula II are useful as tranquilizers and sedatives.

7 Claims, No Drawings N-LDWER ALKENYL-2,3-DIHYDRO-2-OXO-5- PI-IENYL- 1Il-l ,4-BENZODKAZEPINE- l C ARBOXAMIDES BACKGROUND OF THE INVENTIONFIELD OF THE INVENTION This invention is directed to new organiccompounds and is particularly concerned with novel N-sub-'stituted-2,3-dihydro-2-oxo-5-phenyll H-l ,4-benzodiazepin-l-carboxamide, the pharmacologically acceptable acidaddition salts thereof, and a process therefor.

The novel products and the process therefor can be illustrativelyrepresented in the following manner:

wherein R is selected from the group consisting of alkenyl of three toeight carbon atoms, inclusive, cycloalkyl of three to six carbon atoms,inclusive, and haloalkyl in which the alkyl group is of two to sixcarbon atoms, inclusive, and the halogen is fluorine, chlorine, bromine,or iodine; wherein R R R and R are selected from the group consisting ofhydrogen, loweralkyl of one to three carbon atoms, inclusive, fluorine,chlorine, bromine, cyano and trifluoromethyl; and wherein R is hydrogenor alkyl of one to three, carbon atoms, inclusive.

The process ofthis invention comprises: treating a1,3-dihydro-2-oxo-5-phenyl-2I-I-l ,4--benzodiazepine (I) with a reagentselected from the group consisting of alkyl isocyanate, a haloalkylisocyanate and a cycloalkyl isocyanate, in an inert organic solvent, togive the carboxamide of formula II above.

The compounds of formula II are converted to acid addition salts byreacting the earboxamide with the stoichiometrically calculated amountof acid, i.e., one equivalent compound II to one equivalent of acid.Preferably, the reaction is carried out in a water-free medium and withwater-free acid, e.g., hydrogen chloride, or hydrogen bromide dissolvedin methanol or ethanol. Other useful acids are sulfuric, acetic,tartaric, lactic, maleic, citric, and cyclohexanesulfamic acid-DESCRIPTION OF THE PREFERRED EMBODIMENT Lower alkyl groups of one tothree carbon atoms comprise methyl, ethyl, propyl, and isopropyl.

Lower alkenyl groups of three to eight carbon atoms illustrativelyincludes allyl, crotonyl, S-penten-l-yl, 2- penten-l-yl, Z-hexen-l-yl,3-hexen-l-yl; 4-hexen-l-yl; S-hepten-l-yl; 5-octen-l-yl;2-methyl-3-hepten-l-yl; 3- octen-Z-yl; 4-hexen-3-yl, and the like.

Lower haloalkyl groups of two to six carbon atoms are 2-chloroethyl,2-chlorpropyl, 4-chlorobtyyl, 5- bromopentyl, 4-iodopentyl,3-fluoropropyl, 3- bromohexyl, S-chloropentyl, 2-iodoethyl, and thelike.

The cycloalkyl groups herein used are cyclopropyl, cyclubutyl,cyclopentyl, and cyclohexyl.

The novel compounds of the formula Ill including acid addition saltsthereof have sedative, tranquilizing and muscle relaxant effect inmammals and birds.

The acid addition salts of compounds of formula II contemplated in thisinvention, are the hydrochlorides, hydrobromides, hydroiodides,sulfates, phosphates, cyclohexanesulfamates, acetates, lactates,tartrates, citrates, methanesulfonates, and the like, prepared byreacting a compound of formula I with the stoichiometrically calculatedamount of selected pharmacologically acceptable acid.

Sedative effects of N-allyl-7-chloro-2,3-dihydro-2- oxo-S-phenyll H- l,4-benzodiazepine- 1 -carboxamide are shown by the following tests inmice:

Chimney test: [Med. Exp. 4, 11 (1961)]: The effective intraperitonealdosage for 50 percent of mice (ED,,,,) is 0.8 mgjkg. The test determinesthe ability of mice to back up and out of a vertical glass cylinderwithin 30 seconds. At the effective dosage, 50 percent of the micefailed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, 5 cm. high, partiallyembedded in wood shavings), climb out in a very short time when nottreated. Mice remaining in the dish for more than 3 minutes indicatestranquilization. ED equals the dose of test compound at which 50 percentof the mice remain in the dish. The ED (intraperitoneal administration)in this test was 0.8 mgJkg.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than 1 minute. TheED (intraperitoneal administration) is about 0.8 mg. mgjkg.

Nicotine antagonism test: Mice in a group of 6 are injected with thetest compound N-allyl-7-chloro- 2,3-dihydro-2-oxo-5-phenyll H-l ,4-benzodiazepine-l-carboxamide. 30 minutes later the mice includingcontrol (untreated) mice are injected with nicotine salicylate (2mg./kg.). The control mice show overstimulation, i.e., (1) runningconvulsions followed by (2) tonic extensor fits: followed by (3) death.An intraperitoneal dosage of 0.18 mg./kg. of the test compound protected50 percent of the mice against (2) and (3).

Antagonism to strychnine (as sulfate): The effective dosage ED ofN-allyl-7-chloro-2,3-dihydro-2- oxo-S-phenyl-l I-I- l ,4-benzodiazepinel-carboxamide is 5.6 mg./kg. orally in mice. The test consists in orallyadministering into groups of 6 mice the test compound,N-allyl-7-chloro-2,3-dihydro-2- oxo-S-phenyll H- l ,4-benzodiazepine- 1-carboxamide, and 30 minutes later 3 mg./kg. strychnine sulfateintraperitoneally. The survivors after 4 hours reflect the activity ofthe compound as a muscle relaxant and antispasmodic. A dosage of 3mg./kg. of strychnine sulfate is routinely fatal to all the controlmice. The following compounds have (by intraperitoneal injection) ED asshown in the table below:

Ch Chimney Test D Dish test P Pedestal test Ni Nicotine Antagonism (3)test The pharmaceutical forms contemplated by this invention includepharmaceutical compositions suited for oral, parenteral, and rectal use,e.g., tablets, coated and uncoated, powder packets, cachets, dragees,capsules, solutions, suspensions, sterile injectable forms,suppositories, bougies, and the like. Suitable diluents or carriers suchas carbohydrates (lactose), proteins, lipids, calcium phosphate,cornstarch, stearic acid, methylcellulose and the like may be used ascarriers or for coating purposes. Oils, e.g., coconut oil, sesame oil,safflower oil, cottonseed oil, peanut oil, may be used for preparingsolutions or suspensions of the active drug. Sweetening, coloring andflavoring agents may be added.

For mammals and birds, food premixes, with starch, oatmeal, driedfishmeat, fishmeal, flour and the like can be prepared.

As tranquilizer the compounds of formula II can be used in dosages of0.2 mg. to 20 mg./kg. in oral or injectable preparations as describedabove, alleviate tension and anxiety in mammals, or birds, such as e.g.,occurs when animals are in travel.

Other acid addition salts of the compounds of formula II can be made,such as the flurosilicic acid addition salts, which are usefulmothproofing compounds or the trichloroacetates useful as herbicidesagainst Johnson grass, Bermuda grass, yellow foxtail and green foxtail,and quack grass.

The starting materials of formula I of this invention, substituted orunsubstituted 1,3-dihydro- -phenyl-2H- l,4-benzodiazepin-2-ones, areknown. The following compounds of formula I are representative startingmaterials.

l,3-dihydro-5-phenyl-2I-I-l ,4-benzodiazepin-2-one;

6chloro-l ,3-dihydro-5-( m-bromophenyl)-2H- l ,4-

benzodiazepin-Z-one;

7-chloro-l ,3-dihydro-5-phenyl-2H-1,4-

benzodiazepin-Z-one;

8-chloro-l ,3-dihydro-5-phenyl-2I-I-l ,4-

benzodiazepin-Z-one;

benzodiazepin-Z-one;

7-nitro-1 ,3-dihydro-5-phenyl-2I-I-l ,4-benzodiazepin- 2-one;

7-chloro-l ,3-dihydro-5-(3,4-dimethylphenyl)-2I-I-1,4-benzodiazepin-2-one;

l ,3-dihydro-5-(2-methyl-4-chlorophenyl)-2H-1,4-

benzodiazepin-Z-one;

9-bromo-l ,3-dihydro-5-phenyl-2I-I-l ,4-

benzodiazepin-Z-one;

7-methyl-l ,3-dihydro-5-phenyl-2I-I-l ,4-

benzodiazepin-Z-one;

9-nitro-l ,3-dihydro-5-phenyl-2I-I-l ,4-benzodiazepin- 2-one;

9-trifluoromethyl-l ,3-dihydro-5-phenyl-2H-l ,4-

benzodiazepin-Z-one;

8-cyano-l ,3-dihydro-5 -phenyl-2I'I-l ,4-

benzodiazepin-Z-one;

9-cyano-1,3-dihydr0-5-[p-(trifluor0methyl)phenyl]- 2H- 1,4-benzodiazepin-2-one;

7,9-dichloro-l ,3-dihydro-5-(0-chlorophenyl)-2H-1,4-benzodiazepin-2-one;

6,8-dichloro-l ,3-dihydro-5-(o-fluorophenyl )-2I-I- l,4-benzodiazepin-2-one;

7-iodo-l ,3-dihydro-5-(o-fluorophenyl)-2I-I-1,4-

benzodiazepin-Z-one;

3 -methyl-l,3-dihydro-5-(o-fluorophenyl)-2I-I-1,4-

benzodiazepin-Z-one;

7-fluoro-l ,3-dihydro-5-(o-fluorophenyl )-2I-I-1 ,4-

benzodiazepin-Z-one;

3-methyll ,3-dihydro-5-(p-fluorophenyl)-2H-1 ,4-

benzodiazepin-Z-one;

7-nitro-l,3-dihydro-5-(2,4-diodophenyl)-2H-1,4-

benzodiazepin-Z-one;

7,8-dinitro-l ,3-dihydro-5-(o-chlorophenyl )-2l-I- l ,4-

benzodiazepin-Z-one;

7-bromo-l,3-dihydro-5-(o-bromophenyl)-2H-1,4-

benzodiazepin-Z-one;

7-methyl-l ,3-dihydro-5-( 3 ,S-dichlorophenyl )-2H- 1,4-benzodiazepin-2-thione;

7-cyanol ,3-dihydro-5-( 2,4-dibromophenyl )-2H-l,4-benzodiazepine-2-one;

3 ,6,8-trimethyl-l ,3-dihydro-5-( o-chlorophenyD-ZH-1,4-benzodiazepin-2-one;

7-trifluoromethyl-l ,3-dihydro-5-(o-chlorophenyl 2I-I-l,4-benzodiazepin-2-one;

6,7-difluoro-l ,3-dihydro-5-(o-chlorophenyl )-2I-l-1,4-benzodiazepin-2-one;

6-ethyl-l,3-dihydro-5-(2,4-dipropylphenyl)-2I-I-1,4-

benzodiazepin-Z-one;

6,8-diethyl-l ,3-dihydro-5-( m-ethylphenyl)-2H-l ,4-

benzodiazepin-2-one;

3-propyl-6-nitrol ,3-dihydro-5-(o-cyanophenyl)-2H-1,4-benzodiazepin-2-one;

and the like.

In carrying out the process of the invention a selectedl,3-dihydro-5-phenyl-2I-I- I ,4-benzodiazepin- 2 one (I) in an inertorganic solvent, e.g., diethylene glycol, benzene, toluene, xylene,cyclohexane, and

preferably in an ether e.g., tetrahydrofuran, diethyl ether, dipropylether, dibutyl ether, is reacted with the selected isocyanate. Theisocyanates selected include allyl, crotyl, 3-pentenyl, 3-hexenyl,4-heptenyl, 4-octenyl, 2-chloroethyl, 2-bromoethyl, cyclopropyl,

cyclobutyl, cyclopentyl, cyclohexyl isocyanates, and

the like. In the preferred embodiment of this invention he reaction iscarried out in a nitrogen atmosphere, at

the reflux temperature of the mixture but not higher than C. and withthe selected isocyanate in excess i.e., from 5-15 times thestoichiometrically required amount. When the reaction is terminated, themixture is evaporated preferably in vacuo and the resulting product ispurified by conventional procedures e.g., ex-

traction, recrystallization, chromatography, and the like.

The following examples are illustrative of the process and products ofthe present invention.

EXAMPLE 1 N-Allyl-7-chloro-2,3-dihydro2-oxo-5-phenyl-1H-l ,4-benzodiazepine- 1 -carboxamide A solution of 5.42 g. (0.02 mole) of7-chloro-l,3- dihydro-S -phenyl-21-I-1 ,4-benzodiazepin-2-one and 11.7ml. (16.6 g., 0.2 mole) of allyl isocyanate in 75 ml. oftetrahydrofuran, under nitrogen, was stirred under reflux for 21.5hours. The solution as evaporated to dryness in vacuo and purged withtoluene giving a yellow gum. This gum was dissolved in 100 ml. of 2-propanol, filtered hot, concentrated to 50 ml. and cooled giving 4.76 g.(67.5 percent) of white silky needles ofN-a1lyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-11-1-1,4-benzodiazepine-l-carboxamide of melting point 102105 C.

Anal. calcd. for c,,n,,c1N,o,= C, 64.52; H, 4.56; Cl,

9.99;N, 11.88. Found: C, 64.47; H, 4.77; CI, 9.96; N, 12.03.

EXAMPLE 2 7-Chloro-1-(2-chloroethylcarbamoyl)-1,3-dihydro-5-pheny1-2lH-l ,4-benzodiazepin-2-one A solution of 5.42 g. (.02 mole) of7-chloro-1,3- dihydro-5-phenyl-2H-1 ,4-benzodiazepin-2-one, and 7.4 g.(0.07 mole) of 2-chloroethyl isocyanate in 75 ml. of tetrahydrofuranunder nitrogen was stirred at room temperature for 89 hours and thenunder reflux for 96 hours more. More 2-chloroethylisocyanate (total 25g.) was added from time to time. The solution was evaporated in vacuofinally with high vacuum pump giving 8.0 g. of a gum. This gum waschromatographed on 800.0 g. of silica and eluted with 50 percent ethylacetate in cyclohexane. There were collected thirtyone 100-ml.fractions. Fractions 13-17 gave a yellow solid on evaporation, which wasrecrystallized from 2- propanol yielding 2.5 g. (33 percent) of whitecrystals of 7-chloro-l-(2-chloroethylcarbamoyl)-1,3-dihydro-S-phenyl-Zi-ll-l ,4-benzodiazepin-2-one of melting point 1 10l 12 C.

Anal. calcd. for C ii Cl N O C, 57.44; H, 3.98;

Cl, 18.88;N, 11.17. Found: C, 57.70; H, 3,91; Cl, 19.09;N, 11.17.

. EXAMPLE 3 v 7 --Chloro-N-crotyl-2 ,3 -dihydro-2-oxo-5 -phenyl-1Hl- 1,4-benzodiazepinl -carboxamide A solution of 5.42 g. (0.02 mole) of7-chloro-1,3- dihydro-S -phenyl-21'l- 1- ,4-benzodiazepin-2-one and 9.45g. (0.0973 mole) of crotyl isocyanate in 75 ml. of tetrahydrofuran wasstirred under reflux under nitrogen for 84- hours. The solution wasevaporated to dryness in vacuo (finally with a high vacuum pump) at 60C. giving a light yellow gum or glass. This material was dissolved inchloroform, mixed with 10 g. of silica, evaporated and placed on acolumn of 500.0 g. of silica wet with benzene. The column was elutedwith 44-100 ml. portions of 5 percent methanol in benzene. Fractions29-33, inclusive, were combined and evaporated to dryness (weight 5.7g.). This was boiled with cyclohexane, filtered from starting materialand evaporated to a small volume giving a crystalline solid on standing.The fractional crystallization from cyclohexane was repeated twice moregiving 1.7 g. (23 percent) of white crystals of 'l-chloro-Ncrotyl-ZJ-dihydro- 2-oxo-5'phenyl lHd ,4-benzodiazepine-1- carboxamide of meltingpoint 1 14 1 16 C.

Anal. Calcd. for C H CIN O C, 65.31; H, 4,93; Cl,

9.64; n, 11.42. Found: C, 65.46; H, 4,87; Cl, 9.68;N, 11.11.

EXAMPLE 4 N-Allyl-7-cyano-2 ,3 -dihydro-Z-oxo-S-phenyl-11-1-1,4-benzodiazepinel -carboxamide A mixture of 2.1 g. (0.01 mole) of7-cyano-1,3- dihydro-5-phenyl-2l-ll-1,4-benzodiazepin-2-oue, 5.8 ml. ofallyl isocyanate, and 50 ml. of tetrahydrofuran was heated under refluxunder nitrogen with stirring. The solid soon dissolved From time to timemore allylisocyanate was added until a total of about 40 ml. had beenadded. After 68 hours refluxing and 3 days of standing at roomtemperature, about 22-25 C., only a trace of starting material remained.The solution was evaporated to dryness in vacuo and toluene was addedand evaporated giving a crystalline solid residue. This residue wasdissolved in 100 ml. of Z-propanol, filtered hot and concentrated to 70ml. After cooling, the resulting crystals were collected and driedyielding 2.6 g. percent) of yellow crystals of N-a1lyl-7-cyano-2,3-dihydro-2-oxo-5-phenyl-11-ll-1,4-benzodiazepine-1- carboxamide ofmelting point 137.5- 139 C. (dec.).

Anal. Calcd. for czoH oNqozi C, 69.74; H, 4.68; N,

16.27. Found: C, 69.55; H, 4.61; N, 16.66.

EXAMPLE 5 7Ch1oro-N-cyc1opropyl-2,3dihydro2-oxo-5-phenyl- 111-1,4-benzodiazepine- 1 -carboxamide. A. Cyclopropyl isocyanate Asuspension of 35.8 g. (0.55 mole) of dried sodium az ide in 200 ml. oftriethyiene glycol dimethyl ether (triglyme) in a 1 l. flask fitted witha stirrer, thermometer, dropping funnel and a Vigreux column to whichwas attached a Dry ice-cooled, two-necked flask, was cooled to about 5and 52.25 g. (0.5 mole) of cyclopropyl carbonyl chloride (b. p. -117 C.)was added dropwise under nitrogen during 10 minutes at -5 C. Afterstirring at 0 to 25 C. for 1 hour, the

mixture was slowly heated by a water bath. At about 55 C. nitrogenstarted to come off and it was evolved rapidly at 70-l03 C. The flaskwas then heated by an oil bath up to 171 C. and the product wasdistilled at 56 mm Hg. The distillate was redistilled through a 7 feet(one-eighth inch helices packed) column giving 25.67 g. (62 percent)cyclopropyl isocyanate as a liquid of boiling point 87 C. (atrn. press);n 1.4210; d, 1.00.

Anal. Calcd. for Cd-1 140: C, 57.82; H, 6.07; N,

Found: C, 57.02; H, 6.06; N, 17.00. B.7-Chloro-N-cyclopropyl-2,3-dihydro-2-oxo-5-phenyl- 1 i-ll-l,4-henzodiazepine-1-carboxamide A solution of 4.07 g. (0.015 mole) of7-ch1oro-1,3- dihydro-S -phenyl- 1 11-1 ,4-benzodiazepin-l -one and 15g. (15 ml.; 0.18 mole) of cyclopropyl isocyanate (added in threeportions at start, 1 day and 3 days) was stirred under nitrogen underreflux for 5 days. The solution was evaporated to dryness in vacuo,toluene was added and evaporated giving a gurn. This was placed on acolumn of 500 g. of silica and eluted with 1 percent methanol inchloroform. Column fractions 23 to 26 (100 ml. each) were combined,evaporated and recrystallized from cyclohexane, then from 2-propanolgiving 1.7 g. (32 percent) of white crystals of 7-chloro- N-cyclopropyl-2,3-dihydro-2-oxo-S-phenyl-1H-l,4- benzodiazepin-l-carboxamide ofmelting point 142144 C. decomp. with foaming; the melt resolidified atabout 146 and remelted at 21 1-2l3. An analytical sample melted at146-148 C. and remelted at 213.5214.5 C.

Anal. calcd. for C I-I ClN C, 64.50; H, 4.56; CI,

10.02; N, 11.88. Found. C, 64.42; H, 4.49; CI, 10.13; N, 11.81.

EXAMPLE 6 7-Chloro-N-cyclohexyl-2,3-dihydro-2-oxo-5-phenyl- 1H4,4-benzodiazepine-1-carboxamide A solution of 5.42 g. (0.02 mole) of7-chloro-2,3- dihydro--pheny1-1I-I-1,4-benzodiazepin-2-one and 9.77 g.(0.078 mole) ml.) of cyclohexyl isocyanate in 50 ml. of tetrahydrofuranwas stirred under reflux for 6 days. After 1 day, 2 days, 3 days, and 4days 10 ml. more cyclohexylisocyanate was added. The mixture wasevaporated to dryness in vacuo at 1 mm. Hg. Xylene was added andevaporated in vacuo. The residue was dissolved in 185 ml. of 2-propanoland filtered hot; the resulting filtrate was cooled giving 3.65 g. (46percent) of pale yellow crystals of 7-chloro-N-cyclohexyl-Z,3-dihydro-2-oxo-S-phenyl- 1 PH ,4-benzodiazepine-l-carboxamide of melting point 134.5l 36 C.

Anal. calcd. for C I-5 0N 0 C, 66.75; H, 5.60; CI,

895;N, 10.61. Found: C, 66.71; H, 5.64; CI, 9.12; N, 10.66.

EXAMPLE 7 N-(3-Pentenyl)-7-methyl-2,3-dihydro-2-oxo-5-phenyl-1I-I-1,4-benzodiazepine-1-carboxamide In the manner given in Example 1,1,3-dihydro-7- methyl-5phenyl-2I'I-1,4behzodiazepin-2-one can be heatedin tetrahydrofuran solution with 3-pentenyl isocyanate to give,N-(3-penteny1)-7-methyl-2,3-dihydro-2-oxo-5-phenyl-1I-I-1,4-benzodiazepine-1-earboxarnide.

EXAMPLE 8N--(3-Hexenyl)-7,9-dichloro-2,3'dihydro-2-oxo-5-(ochlorophenyl)-1H-1,4-benzodiazepine-l-carboxamide1n the manner given in Example 1, 1,3-dihydro-7,9- dichloro-5-(o-chlorophenyl)-2H-l ,4-benzodiazepin-2- one can be heated intetrahydrofuran solution with 3- hexenyl siocyanate to giveN-(3-hexenyl)-7,9-dichloro-2,3-dihydro-2-oxo-5-(o-chlorophenyl)-III-1,4-benzodiazepine-lCarboxamide.

EXAMPLE 9N-(4-octenyl)-7-fluoro-2,3-dihydro-2-oxo-5-(ofluorophenyl)-11-I-l,4-benzodiazepine-l-carboxamideIn the manner given in Example 1, 1,3-dihydro-7-fluoro-S-(o-fluorophenyl)-2I'I-1,4-benzodiazepine-2- one can be heatedin tetrahydrofuran solution with 4- octenyl isocyanate to giveN-(4-octenyl)-7-fluoro-2,3-

dihydro-2-oxo-5-(o-fluorophenyl)-III-1,4- benzodiazepine- 1 -carboxamide.

EXAMPLE 10 8-Cyano-1-(3-chloropropylcarbamoyl)-1,3-dihydro-2-oxo-5-phenyl-lH-1,4-benzodiazepin-2-one In the manner given in Example2, 1,3-dihydro-8- cyano-5-phenyl-2I-I-1,4-benzodiazepin-2-one can beheated in tetrahydrofuran solution with 3-chloropropyl isocyanate togive 8-cyano-l-(3-chloropropylcarbamoyl)-1,3-dihydro-2oxo-5-phenyl-1H-l,4- benzodiazpin-Z-one.

EXAMPLE 1 1 EXAMPLE 12 7-Trifluoromethyl-(4-ch1oropentylcarbamoyl)-2,3-dihydro-5-(o-chlorophenyl)-1I-I-1,4-benzodiazepin-2- one In the mannergiven in Example 2, 1,3-dihydro-7-trifluoromethyl-S-(o-chlorophenyl)-2H-l ,4- benzodiazepin2-one can beheated in tetrahydrofuran solution with4-chloropentylcarbamoyl)-2,3-dihydro-5- (o-chloropentyl)-1 I'l-l,4-benzodiazepin-2-one.

EXAMPLE l3 6,8-Diethyl-(6-iodohexylcarbamoyl)-2,3-dihydro-5-(m-ethylphenyl)-1I-I-1,4-benzodiazepin-2-one.

In the manner given in Example 2, 1,3-dihydro-6,8-diethyl-5-(m-ethylphenyl)-2I'I-1,4-benzodiazepin-2- one can be heated intetrahydrofuran solution with 6- iodohexyl isocyanate to give6,8-diethyl-(6-iodohexylcarbamoyl)-2,3-dihydro-5-(m-ethylphenyl)-lI-I-1,4-benzodiazepin-Z-one.

EXAMPLE 14 N-crotyl-7-bromo-2,3-dihydro-2-oxo-S-phenyl-1H-1 ,4-benzodiazepine-l-carboxamide.

In the manner given in Example 1, 1,3-dihydro-7-bromo-5-phenyl-21-I-1,4-benzodiazepin-2-one can be heated intetrahydrofuran solution with crotyl isocyanate to giveN-crotyl-7-bromo-2,3-dihydro-2-oxo-5- phenyl-l H-l ,4benzodiazepinel-carboxamide.

EXAMPLE 15 [(5-Bromohex-2-yl)carbamoyl]-3-methyl-2,3-dihydro- 2-oxo-5-(o-fluorophenyl)-1H-1,4-benzodiazepin-2-one In the manner given inExample 2, 1,3-dihydro-3- methyl-S-(o-fluorophenyl)-2H-1-benzodiazepin-2- one can be heated in tetrahydrofuran solution with (5-bromohex-2-yl) isocyanate to give [(S-bromohex-Z-yl)carbamoyl]-3-methyl-2,3-dihydro-2-oxo-5-phenyl-1 I-I-l,4-benzodiazepin-2-one.

EXAMPLE 16N-cyclopropyl-6,7-difluoro-2,3-dihydro-2-oxo-5-(ochlorophenyl)-lH-1,4-benzodiazepine-1-carboxamidechloropentyl 1 ,4-benzodiazepin3- l -carboxamide.

EXAMPLE l7 6,8-diethyl-l 3-chloropentylcarbamoyl)-2,3-dihydro-2-oxo-5-(m-ethylphenyl)-lH-l,4-benzodiazepin-2-one.

In the manner given in Example 2, l,3-dihydro-6,8-diethyl-S-(m-ethylphenyl)-2H-l ,4-benzodiazepin-2- one can be heated intetrahydrofuran solution with 3- isocyanate to give 6,8-diethyl-l-(3-chlorOpentylcarbamoyU-Z,3-dihydro-2-oxo-5-(methylphenyl l H-l,4-benzodiazepine-2-one.

In the manner given in the preceding examples, other2,3-dihydro-2-oxo-5-phenyl-1,4-benzodiazepin-l-carboxamide of formula llcan be obtained by reacting a 1,3-dihydro-5-phenyl-2H- l,4-benzodiazepin'2-one l with" a alkenyl, haloalkyl ro cycloalkylisocyanate as described. Representative compounds thus prepared,include:

N-allyl-3-propyl-6-nitro-2,3-dihydro-2-oxo-5-(ocyanophenyl)-lH-l,4-benzodiazepine-l-carboxamide;

N-(3-hexenyl)-3,6,8-trirnethyl-2,3-dihydro-2-oxo-5-(o-chlorophenyl)-2H-l ,4-benzodiazepine- 1 -carboxarnide;

N-(3-heptenyl)-7-chloro-2,3-dihydro-2-oxo-5-(3,4-

dimethylphenyl)-1H-l ,4-benzodiazepine-l-carboxamide;

N-(3-0cten-6-yl)-7-trifluoromethyl-2,3-dihydro-2- oxo-S -phenyl-l H-l,4-benzodiazepine- 1 -carboxamide;

N-cyclopropyl-7-fluoro-2,3-dihydro-2-oxo-5-phenyliH-l ,4-benzodiazepinel-carboxamide;

N-cyclobutyl-8-cyano-2,3-dihydro-2-oxo-5-phenylllH- 1 ,4-benzodiazepinel-carboxamide;

N-cyclohexyl-9-cyano-2,3-dihydro-2-oxo-5-phenyl-[p-trifluoromethylphenyl]-lH-l ,4- benzodiazepine-l-carboxamide;

N-cyclbpentyl-Z,3-dihydro-2-oxo-5-phenyl- 1 H-1 ,4-

benzodiazepine-l -carboxamide;

I 1-( 3iodobutylcarbamoyl )-7 ,9-dichloro-2,3-dihydro-2-oxo-5-(o-chlorophenyl )-2H-l ,4-benzodiazepin- 2-one:

1-( 4-fluoropentylcarbamoyl )-3-m ethyl-l ,3dihydro- 2-oxo-5-(o-fluorophenyl )-2H-l ,4-benzodiazepin- 2-one;

and the like.

I claim:

1. A 2,3-dihydro-2-oxo-5-phenyl-ll-l-l ,4

benzodiazepinl carboxamide of the formula (II):

wherein R, is selected from the group consisting of alkenyl of three toeight carbon atoms, inclusive, cycloalkyl of three to six carbon atoms,inclusive, and haloalkyl in which the alkyl group is of two to sixcarbon atoms, inclusive, nd the halogen is fluorine, chlorine, bromine,or iodine; wherein R R R and R are selected from the group consisting ofhydrogen, alkyl of one to three carbon atoms, inclusive, fluorine,chlorine, bromine, cyano, and trifluoromethyl; and wherein R is hydrogenor alkyl of one to three, carbon atoms, inclusive, and thepharmacologically acceptable addition salts thereof.

2. N-Allyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H- l ,4-benzodiazepinel-carboxamide.

3. 7-Chloro-N-crotyl-2,3-dihydro-2-oxo-5-phenylll-l-l,4-benzodiazepine-l -carboxamide.

4. N-allyl-7-cyano-2,3-dihydro-2-oxo-5-phenyl-1H- 1 ,4-benzodiazepinel-carboxamide.

5. 7-Chloro-N-cyclopropyl-2,3-dihydro-2-oxo-5- phenyl- 1 H-l,4-benzodiazepinel -carboxamide.

6. 7-Chloro-N-cyclohexyl-2 ,3-dihydro-2-oxo-5 phenyl- 1 l-l-l,4-benzodiazepinel -carboxamide.

7. 7-Chloro-1-(2-chloroethylcarbarnoyl)-1,3-

dihydro-S-phenyl-ZH-l,4-benzodiazepin-2-one.

2. N-Allyl-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-carboxamide. 3.7-Chloro-N-crotyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-carboxamide. 4.N-allyl-7-cyano-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-carboxamide. 5.7-Chloro-N-cyclopropyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-carboxamide. 6.7-Chloro-N-cyclohexyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-carboxamide. 7.7-Chloro-1-(2-chloroethylcarbamoyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one.